Animal feed and process

ABSTRACT

AN ANIMAL FEED COMPRISING A COMPOUND OF THE GROUP CONSISTING OF A 1-SUBSTITUTED-6-PHENYL-4H-S-TRIAZOLO(4,3,-A) (1,4)BENZODIAZEPINE OF THE FORMULA:   1-R,4-R1,6-(R2,R3-PHENYL),R4,R5-4H-S-TRIAZOLO(4,3-A)-   1,4-BENZODIAZEPINE   WHEREIN R IS SELECTED FROM THE GROUP CONSISTING OF THIO, ALKYLTHIO, IN WHICH THE ALKYL GROUPS IS OF 1 TO 3 CARBON ATOMS, INCLUSIVE, AMINO, NITRO, AND FLUORO; WHEREIN R1 IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN AND ALKYL, DEFINED AS ABOVE, AND WHEREIN R2, R3, R4 AND R5 ARE SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, ALKYL, DEFIND AS ABOVE, HALOGEN, NITRO, CYANO, TRIFLUOROMETHYL, AND ALKOXY, ALKHLTHIO, ALKYLSULFINYL, AND ALKYLSUFONYL, IN WHICH THE CARBON CHAIN MOIETIES ARE OF 1 TO 3 CARBON ATOMS, INCLUSIVE, AND THEIR PHARMACOLOGICALLY ACCEPTABLE ACID ADDITION SALTS AND N-5 OXIDES IN COMBINATION WITH NUTRIENT FEEDS.

United States Patent Oflice Patented Apr. 9, 1974 3,803,315 ANIMAL FEEDAND PROCESS Robert J. Collins, Portage, Mich., assiguor to The UpjohnCompany, Kalamazoo, Mich. No Drawing. Filed Aug. 9, 1971, Ser. No.170,322 5 Int. Cl. A611: 27/00 U.S. Cl. 424-269 6 Claims ABSTRACT OF THEDISCLOSURE An animal feed comprising a compound of the group consistingof a 1-substituted-6-phenyl-4H-s-triazolo[4,3-a] [1,41benzodiazepine ofthe formula:

R-{aQ s/itv l s 1 \L g R: Formuial wherein R is selected from the groupconsisting of thio, alkylthio, in which the alkyl group is of 1 to 3carbon atoms, inclusive, amino, nitro, and fluoro; wherein R is selectedfromthe group consisting of hydrogen and alkyl, defined as above, andwherein R R R and R are selected from the group consisting of hydrogen,alkyl, defined as above, halogen, nitro, cyano, trifiuoromethyl, andalkoxy, alkylthio, alkylsulfinyl, and alkylsulfonyl, in which the carbonchain moieties are of 1 to 3 carbon atoms, inclusive, and theirpharmacologically acceptable acid addition salts and N-S oxides incombination with nutrient feeds.

CROSS REFERENCE TO RELATED APPLICATIONS This application is related tocopending United States application Ser. No. 138,290, filed Apr. 28,1971, now Pat. No. 3,751,426, which discloses compounds of the Formula 1and methods for their preparation.

BRIEF SUMMARY OF THE INVENTION DETAILED DESCRIPTION It has been found inrecent years that meat-producing animals will gain more weight and gainit faster when various classes of compounds such as vitamins, minerals,estrogens, antibiotics, and tranquilizers are added to the diet.Although the presently available compounds are useful, new materials arestill being sought that would produce weight gains more rapidly, to agreater extent, more efficiently with respect to feed intake at a lowercost and without undesirable side effects.

It is now possible by use of the present invention to obtain unexpectedresults in the feeding of meat-producing, milk-producing, or egg-layinganimals; that is to say, an increased rate of weight gain, an increasedamount of weight gain, an increase in milk production, or increased rateof egg laying, as well as increased feed efficiency, can be obtained bythe addition of minute quantities of a compound of the Formula 1 to theanimals usual nutrient feed.

Compounds of the Formula 1 can be prepared by methods disclosed inUnited States application Ser. No. 138,290, filed Apr. 28, 1971, nowPat. No. 3,751,426.

Unless otherwise specified, all percentages are given on aweight-to-weight basis. The pound (1b.) weights given are avoirdupoisunits.

Feeding of the compositions of the present invention can commence forbirds shortly after hatching and in the case of mammals, during thecreep-feeding period of suckling animals when they are starting on solidfood and, of course, after weaning. Feeding of the compositions iscontinued throughout the growing period, lactation period, or egg-layingperiod.

The total concentration of the compound of the Formula 1 in the feedcomposition is determined with regard to the species of animal, age,weight, and average amount of feed consumed daily. Preferably thecompound of the Formula 1 is employed in the finished feed that willsupply the animal with a daily'intake of from about 0.015 mg. to about250 mg. per head per day.

The following table illustrates the range of compound of Formula 1 inmilligrams daily dose per head per day for representative animals.

The foregoing dosage can generally be accomplished by providing fromabout mg. to about 12,500 mg. of a compound of the Formula 1 per ton offinished feed.

Advantageously a compound of the Formula 1 is supplied in the form of aliquid or solid premix wherein the concentration is -2000 times greaterthan the desired final concentration of the feed. For example, thecompound of Formula 1 can be dissolved or suspended in a :fluid vehiclesuch as corn oil, cottonseed oil, molasses, distillers solubles and thelike to prepare a fluid premix. Alternatively, a solid premix can beprepared by mixing a compound of the Formula 1 with an edible soliddiluent such as sucrose, lactose, starch, corn meal, flour, calciumcarbonate, soybean meal and the like.

3 EXAMPLE 1 A diet for fattening lambs is prepared from the followingtypes and amounts of ingredients:

Percent Ground ear corn 82.05 Alfalfa meal 10.0 Soybean oil meal 44% 7.0Ground limestone 0.3 Salt 0.6 Trace mineral mixture 1 0.05

Contains the following percent of minerals: Mn, 12; Co, 0.08; Fe, 5.0:Cu. 0.4; I, 0.24 Zn, 0.7.

A chicken feed for broilers is prepared from the following types andamounts of ingredients:

Percent Yellow corn meal 67.35

Soybean oil meal 24.00

Menhaden fish meal 6.00 Steamed bone meal 1.00 Ground limestone 1.00Iodized salt .34 25% choline chloride .13 Vitamin B supplement (6 mg./lb.) .10 Manganese sulfate .02 Supplemental vitamin mix 1 .06

1 Consisting of 16.0 gm. Vitamin A supplement units/ mg); 3.6 gm.Vitamin D3 supplement (15,000 units/gun); 7.1 gm. riboflavin supplement(1 gm. riboflavin per ounce); 500 gm. niacin.

A fattening feed for 800 pound yearling cattle is prepared from thefollowing types and amounts of ingredients:

Percent Ground ear corn 89.75 Soybean oil meal, 44% 9.0 Ground limestone0.7 Salt 0.5 Trace mineral mixture 1 0.05

1 Contains the following percent of minerals: Mn, 12; Co, 0.08; Fe, 5.0;Cu, 0.4 I, 0.24; Zn, 0.7.

To 999 parts of the preceding feed is added 1 part of a premixcomposition prepared by mixing 1.5 gm. of 8- chloro 6phenyl-4H-s-triazolo[4,3-a][l,4]benzodiazepine-l-thiol with sufiicientwheat flour to make 1 pound.

The feeding composition so prepared supplies 1.5 mg. of S-chloro 6phenyl-4H-s-triazolo[4,3-a][1,-4]benzodiazepine-l-thiol per pound, orabout 3.3 parts per million.

Cattle are to receive the foregoing feed ad libitum together with 5 lb.of hay per head per day and when so fed have an increased rate of weightgain and improved utilization of feed.

EXAMPLE 4 A swine diet for growing hogs of 40 to pounds body weight isprepared from the following types and amounts of ingredients:

Percent Corn, ground 78.15 Soybean oil meal, 44% 17.0 Meat and bonescraps, 50% 3.0 Oyster shell flour 0.4 Bone meal 0.5 Salt 0.5 Tracemineral mixture 1 0.05 Zinc oxide 0.01 Vitamin A and D supplement 2 0.25Vitamin B supplement 0.05 Vitamin B supplement 4 0.09

1 Contains the following percent of minerals: Mn, 12; Co, 0.08; Fe, 5.0Cu, 0.4 I, 0.24 Zn, 0.7.

Contains 300 USP units Ds/Gm. and 1500 I.U.A./Gm.

3 Contains per lb. Riboflavin, 2000 mg. calcium pantothenate, 4000 mg.;niacin, 9000 mg.; and choline chloride 10,000

4 Contains 6 mg. Vitamin B12 per lb.

To 999 parts of the preceding feed is added 1 part of a premixcomposition prepared by mixing 0.75 gm. of 8- chloro 6phenyl-4H-s-triazolo[4,3-a][1,41benzodiazepine-l-thiol with sufiicientground limestone to make one pound.

The feeding composition so prepared supplies 0.75 mg. of S-chloro 6phenyl-4H-s-triazolo[4,3-a] [1,4]benzodiazepine-l-thiol per pound, orabout 1.65 parts per million.

The foregoing composition is usefully fed to hogs for increased rate ofweight gain and improved utilization of feed.

EXAMPLE 5 Following the procedure of the preceding Examples 1 to 4,inclusive, animal feeds are similarly prepared substituting equimolaramounts of:

S-nitro-6-phenyl-4H-s-triazolo [4, 3-a] 1,4] benzodiazepine- 1 -thiol;

8-chloro-6- (o-chlorophenyl) -4H-s-triazolo [4,3-a] 1 ,4]

benzodiazepine-l-thiol;

8-chloro-6-( 2,6-difluorophenyl) -4H-s-triazolo- [4,3-a1-[1,4]benzodiazepine-1-thiol;

6- (o-chlorophenyl) -4H-s-triazolo [4,3-a] 1,4] benzodiazepinel -thiol;

8-methylsulfinyl-6-phenyl-4H-s-triazolo [4,3-a] 1,4]

benzodiazepinel-thiol;

8,9-dicyano-6- (p-isopropylphenyl) -4H-s-triazolo [4,3 -a] [1,4]benzodiazepine-l-thiol;

4,7,9-trimethyl-6- (o-chlorophenyl) -4H-s-triazolo [4,3-a]

[ 1,4] benzodiazepinel-thiol;

7,9-diethy1-6-(m-ethylphenyl -4H-s-triazolo [4,3 -a] [1,4]benzodiazepine-l-thiol;

10-propylsulfonyl-8-methyl-6-phenyl-4H-s-triazolo- [4,3-a] [1,4]benzodiazepine-l-thiol;

8-chloro-1- (methylthio -6-phenyl-4H-s-triazolo [4,3 -a][1,4]benzodiazepine;

8-nitro-1-(propylthio) -6-phenyl-4H-s-triazolo [4,3-a]

[ 1,4]-benzodiazepine',

8-chloro- 1- (ethylthio) -6- (o-chlorophenyl) -4H-s-triazolo- [4,3-a][1,4] benzodiazepine;

S-chloro- 1- (methylthio -6- 2,6-difluorophenyl) -4H-striazolo [4,3-a][1,4] benzodiazepine;

1- (isopropylthio )-6- (o-chlorophenyl) -4H-striazolo- [4,3-a][1,41benzodiazepine;

8-methylsulfinyl-1-(ethylthio)- 6-phenyl-4H-s-triazolo- [4,3-a] [1,4]benzodiazepine;

8,9-dicyano- 1-( propylthio -6- (isopropylphenyl) -4H-striazolo [4,3-a]1,4] benzodiazepine;

